The present application is based on Japanese Application No. Hei. 10-223724, which is incorporated herein by reference.
The present invention relates to a process for the preparation of a 4-substituted azetidinone derivative which is important as an intermediate for the synthesis of a carbapenem compound.
Since a 1-xcex2-methylcarbapenem derivative exhibits excellent antibacterial activity against a wide range of bacteria including Gram positive bacteria and Gram negative bacteria and has excellent in vivo stability, it has attracted attentions as an antibacterial agent. For the synthesis of this 1-xcex2-methylcarbapenem derivative, various processes are known. In particular, an azetidinone compound having a xcex2-methyl group at the 1xe2x80x2-position of the 4-side chain, said compound being represented by the following formula (A): 
wherein R1 represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group, is an especially important intermediate for the synthesis of the derivative. It has so far been synthesized by a 1xe2x80x2-deprotonation of the acetic acid residue at the 4-position by using a strong base and then introducing a methyl group [Heterocycles, 21, 29(1984)]. By the above-described process, however, it is difficult to stereo-selectively prepare a compound having a xcex2-configuration at the 1xe2x80x2-position of the 4-side chain. Various processes are therefore proposed now.
For example, Fuentes, et al. has proposed a process in which a 4-acetoxyazetidinone compound and a certain propionamide derivative are reacted in the presence of a reagent complex composed of a certain base and a Lewis acid, for example, tin triflatexe2x80x94ethylpiperidinexe2x80x94zinc bromide or diethylborane triflatexe2x80x94diisopropylethylaminexe2x80x94zinc bromide [L. M. Fuentes, et al., J. Am. Chem. Soc., 108, 4675(1986), JP-A-61-275267 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d)]. A similar process has been proposed by Nagao, et al. [Y. Nagao, et al., J. Am. Chem. Soc., 108, 4673(1986), JP-A-63-170377] and also by Hara, et al. [WO 93/13064, JP-A-7-70116]. Iwasaki, et al. has proposed a process in which reaction is performed in the presence of a predetermined base [JP-A-7-97381].
The above-described process using a reagent complex of a base and a Lewis acid however lacks in environmental harmony because as the Lewis acid, that containing an expensive boron reagent or a heavy metal is employed. It is therefore impossible to deny the industrial disadvantage of this process. In addition, the use of a predetermined base, for example, a base typically employed in this is reaction such as sodium or lithium brings about a marked decrease in the yield under the reaction conditions at around room temperature. Very low temperature conditions at xe2x88x9260xc2x0 C. or lower become essential, which also makes the process industrially disadvantageous.
With a view to overcoming the above-described problems of the conventional process and to finding a process permitting the selective preparation of an intermediate for the synthesis of a carbapenem antibacterial agent having a desired 1xe2x80x2-xcex2 configuration, the present inventors have proceeded with various investigations. As a result, it has been found that a compound having a desired 1xe2x80x2-xcex2 configuration can be prepared only by reacting in the presence of a predetermined magnesium compound without using a reagent complex of a base and a Lewis acid as described in the conventional process or without using a base requiring predetermined low-temperature reaction conditions.
In the present invention, there is provided a process for selectively preparing a desired 1xe2x80x2-xcex2 configuration, which comprises reacting an azetidinone compound and a predetermined alkanamide compound in the presence of a magnesium compound without using a reagent complex composed of a base and a Lewis acid or a base which requires predetermined low-temperature reaction conditions.
Described specifically, the present invention provides a process for the preparation of a 4-substituted azetidinone derivative represented by the following formula (IV): 
wherein R represents a hydrogen atom or a protecting group for N, R1 represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group, R2 represents a hydrogen atom or a lower C1-4 alkyl group, R3 represents (1) a C1-12 alkyl group, (2) a C2-5 alkenyl group, (3) a C1-6 organosilyl group, (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (5) a C6-13 aralkyl group which may be substituted by a lower C1-4 alkyl group, (6) a 5- to 8-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (7) a naphthyl group, and R4 represents an electron withdrawing group; or R3 and R4 may form a heterocyclic ring together with the adjacent nitrogen atom,
which comprises reacting an azetidinone derivative represented by the following formula (I): 
wherein R represents a hydrogen atom or a protecting group for N, R1 has the same meaning as described above, Z represents an eliminative group,
with an amide compound represented by the following formula (II): 
wherein R2, R3 and R4 have the same meanings as described above,
in the presence of a magnesium compound represented by the following formula (III):
MgR5R6xe2x80x83xe2x80x83(III)
wherein R5 represents (1) a C1-12 alkyl group, (2) a C2-5 alkenyl group, (3) a 5- to 8-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group or a halogen atom, or (5) a benzyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group or a halogen atom, and R6 represents (1) a halogen atom, (2) a methanesulfonyloxy group, (3) a benzenesulfonyloxy group, (4) a p-toluenesulfonyloxy group, (5) a trifluoromethanesulfonyloxy group, (6) an acetoxy group which may be substituted by a halogen atom or a cyano group, or (7) an OR7 group wherein R7 represents a lower C1-4 alkyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group.
The present invention will next be described more specifically.
In the formula (I) of the present invention, R represents a hydrogen atom or a protecting group for N, R1 represents a lower alkyl group which may be substituted by a protected or unprotected hydroxyl group and Z represents an eliminative group.
Specific examples of the protecting group for N include organosilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylhexylsilyl and dimethylthexylsilyl, a benzyl group, a p-nitrobenzyl group, a p-nitrobenzoylmethyl group, a benzhydryl group, a p-methoxybenzyl group and a 2,4-dimethoxybenzyl group.
Specific examples of the protecting group for the hydroxyl group which is a substituent of the lower alkyl group represented by R1 include organosilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylhexylsilyl, trimethylsilyl and dimethylthexylsilyl; oxycarbonyl groups such as p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and allyloxycarbonyl; an acetyl group; a triphenylmethyl group; a benzoyl group and a tetrahydropyranyl group.
Here, the lower alkyl group of R1 means a lower C1-4 alkyl group and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl, with the ethyl being preferred.
Preferred specific examples of R1 include 1-tert-butyldimethylsilyloxyethyl, 1-tert-butyldiphenylsilyloxyethyl, 1-triethylsilyloxyethyl, 1-triisopropylsilyloxyethyl, 1-trimethylsilyloxyethyl, 1-dimethylthexylsilyloxyethyl and 1-hydroxyethyl, of which the 1-tert-butyldimethylsilyloxyethyl is particularly preferred.
Examples of the eliminative group of Z include acyloxy groups (ex. alkanoyloxy, aroyloxy, arylalkanoyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkoxycarbonyloxy, aralkoxycarbonyloxy, alkoxyalkanoyloxy and carbamoyloxy), thionyl groups (ex. alkanoylthio, aroylthio, alkylthio and arylthio), sulfinyl groups (ex. alkylsulfinyl and arylsulfinyl), sulfonyl groups (ex. alkylsulfonyl and arylsulfonyl) and halogen atoms.
When Z represents an alkanoyloxy group, specific examples of it include linear alkanoyloxy groups each of which may be substituted by a halogen atom or a cyano group, for example, acetoxy, propionyloxy, butyryloxy, xcex1-fluoroacetoxy, xcex1-chloroacetoxy, xcex1-bromoacetoxy, xcex1-iodoacetoxy, xcex1,xcex1-difluoroacetoxy, xcex1,xcex1-dichloroacetoxy and xcex1-cyanoacetoxy, and branched or cyclic alkanoyloxy groups such as isobutyryloxy and cyclohexylcarbonyloxy.
When Z represents an aroyloxy group, specific examples of it include monocyclic or bicyclic aroyloxy groups which may contain a hetero atom, such as benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, nicotinoyloxy, isonicotinoyloxy and flufuroyloxy.
When Z represents an arylalkanoyloxy group, specific examples include arylalkanoyloxy groups such as phenylacetoxy.
When Z represents an alkylsulfonyloxy group, specific examples include alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and trifluoromethanesulfonyloxy.
When Z represents an arylsulfonyloxy group, specific examples include arylsulfonyloxy groups such as benzenesulfonyloxy and toluenesulfonyloxy.
When Z represents an alkoxycarbonyloxy group, specific examples of it include alkoxycarbonyloxy groups such as methoxycarbonyloxy and ethoxycarbonyloxy.
When Z represents an aralkoxycarbonyloxy group, specific examples include aralkoxycarbonyloxy groups such as benzyloxycarbonyloxy.
When Z represents an alkoxyalkanoyloxy group, specific examples include alkoxyalkanoyloxy groups such as methoxyacetoxy and ethoxyacetoxy.
When Z represents a carbamoyloxy group, specific examples include carbamoyloxy groups such as N-methylcarbamoyloxy, N-ethylcarbamoyloxy and N-phenylcarbamoyloxy.
When Z represents an alkanoylthio group, specific examples include alkanoylthio groups such as acetylthio and propinylthio.
When Z represents an aroylthio group, specific examples include aroylthio groups such as benzoylthio.
When Z represents an alkylthio group, specific examples include alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio and tert-butylthio.
When Z represents an arylthio group, specific examples include arylthio groups such as phentylthio.
When Z represents an alkylsulfinyl group, specific examples include alkylsulfinyl groups such as methanesulfinyl, ethanesulfinyl, propanesulfinyl and butanesulfinyl.
When Z represents an arylsulfinyl group, specific examples include arylsulfinyl groups such as benzenesulfinyl and toluenesulfinyl.
When Z represents an alkylsulfonyl group, specific examples include alkylsulfonyl groups such as methanesulfonyl, ethanesulfonyl, propanesulfonyl and butanesulfonyl.
When Z represents an arylsulfonyl group, specific examples include arylsulfonyl groups such as benzenesulfonyl.
When Z represents a halogen atom, specific examples include halogen atoms such as fluorine, chlorine and bromine.
As the particularly preferred example of Z, an acetoxy group can be mentioned by way of example.
There is no particular limitation imposed on the preparation process of the azetidinone derivative of the formula (I). It can be prepared, for example, by the process as described in Shun-Ichi Murahashi, et al., J. Am. Chem. Soc., 112, 7820-782:2(1990), Shun-Ichi Murahashi, et al., Tetrahedron Letters, 32, 2145-2148(1991), or Shun-Ichi Murahashi, et al., Tetrahedron Letters, 32, 5991-5994(1991) or in a similar manner thereto.
Specific examples of the azetidinone derivative of the formula (I) include the following compounds:
4-acetoxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,
4-acetoxy-3-[1-tert-butyldiphenylsilyloxyethyl]-azetidin-2-one,
4-acetoxy-3-[1-triethylsilyloxyethyl]-azetidin-2-one,
4-acetoxy-3-[1-trimethylsilyloxyethyl]-azetidin-2-one,
4-acetoxy-3-[1-dimethylthexylsilyloxyethyl]-azetidin-2-one,
4-acetoxy-3-[1-hydroxyethyl]-azetidin-2-one,
4-isobutyryloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,
4-propionyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one, and
4-benzoyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one, of which the 4-acetoxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one is preferred.
In the magnesium compound of the formula (III) in the present invention, R1 represents (1) a C1-12 alkyl group, (2) a C2-4 alkenyl group, (3) a 5- to 8-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group or a halogen atom, or (5) a benzyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group or a halogen atom. R6 represents (1) a halogen atom, (2) a methanesulfonyloxy group, (3) a benzenesulfonyloxy group, (4) a p-toluenesulfonyloxy group, (5) a trifluoromethanesulfonyloxy group, (6) an acetoxy group which may be substituted by a halogen atom or a cyano group, or (7) an OR7 group wherein R7 represents a lower C1-4 alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group.
Here, specific examples of R5 of the magnesium compound (III) include (1) C1-12 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, (2) C2-4 alkenyl groups such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 2-methylallyl, (3) 5- to 8-membered alicyclic groups, each of which may have a substituent, such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl (here, the substituent being a lower C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl), and (4), (5) phenyl groups each of which may have a substituent and benzyl groups each of which may have a substituent (here, the substituent being a lower C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, a lower C1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine).
Specific examples of R6 include (1) halogen atoms such as fluorine, chlorine, bromine and iodine, (2) a methanesulfonyloxy group, (3) a benzenesulfonyloxy group, (4) a p-toluenesulfonyloxy group, (5) a trifluoromethanesulfonyloxy group, (6) acetoxy groups each of which may be substituted by a halogen atom or a cyano group (here, specific examples include xcex1-fluoroacetoxy, xcex1-chloroacetoxy, xcex1-bromoacetoxy, xcex1-iodoacetoxy, xcex1, xcex1-difluoroacetoxy, xcex1,xcex1-dichloroacetoxy and xcex1-cyanoacetoxy), and (7) OR7 groups (here, specific examples of R7 include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, substituted or unsubstituted phenyl groups and substituted or unsubstituted benzyl groups (the substituent being a lower C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, a lower C1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine).
Specific examples of the magnesium compound represented by the formula (III) include methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, methylmagnesium methanesulfonate, methylmagnesium p-toluenesulfonate, methylmagnesium methoxide, methylmagnesium ethoxide, methylmagnesium tert-butoxide, methylmagnesium phenoxide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, ethylmagnesium methanesulfonate, ethylmagnesium p-toluenesulfonate, ethylmagnesium methoxide, ethylmagnesium ethoxide, ethylmagnesium tert-butoxide, ethylmagnesium phenoxide, propylmagnesium chloride, propylmagnesium bromide, propylmagnesium iodide, propylmagnesium methanesulfonate, propylmagnesium p-toluenesulfonate, propylmagnesium methoxide, propylmagnesium ethoxide, propylmagnesium tert-butoxide, propylmagnesium phenoxide, iso-propylmagnesium chloride, iso-propylmagnesium bromide, iso-propylmagnesium iodide, iso-propylmagnesium methanesulfonate, iso-propylmagnesium p-toluenesulfonate, iso-propylmagnesium methoxide, iso-propylmagnesium ethoxide, iso-propylmagnesiumn tert-butoxide, iso-propylmagnesium phenoxide, n-butylmagnesium chloride, n-butylmagnesium bromide, n-butylmagnesium iodide, n-butylmagnesium methanesulfonate, n-butylmagnesium p-toluenesulfonate, n-butylmagnesium methoxide, n-butylmagnesium ethoxide, n-butylmagnesium tert-butoxide, n-butylmagnesium phenoxide, iso-butylmagnesium chloride, iso-butylmagnesium bromide, iso-butylmagnesium iodide, iso-butylmagnesium methanesulfonate, iso-butylmagnesium p-toluenesulfonate, iso-butylmagnesium methoxide, iso-butylmagnesium ethoxide, iso-butylmagnesium tert-butoxide, iso-butylmagnesium phenoxide, sec-butylmagnesium chloride, sec-butylmagnesium bromide, sec-butylmagnesium iodide, sec-butylmagnesium methanesulfonate, sec-butylmagnesium p-toluenesulfonate, sec-butylmagnesium methoxide, sec-butylmagnesium ethoxide, sec-butylmagnesium tert-butoxide, sec-butylmagnesium phenoxide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, tert-butylmagnesium iodide, tert-butylmagnesium methanesulfonate, tert-butylmagnesium p-toluenesulfonate, tert-butylmagnesium methoxide, tert-butylmagnesium ethoxide, tert-butylmagnesium tert-butoxide, tert-butylmagnesium phenoxide, cyclopentylmagnesium chloride, cyclopentylmagnesium bromide, cyclopentylmagnesium iodide, cyclopentylmagnesium methanesulfonate, cyclopentylmagnesium p-toluenesulfonate, cyclopentylmagnesium methoxide, cyclopentylmagnesium ethoxide, cyclopentylmagnesium tert-butoxide, cyclopentylmagnesium phenoxide, cyclohexylmagnesium chloride, cyclohexylmagnesium bromide, cyclohexylmagnesium iodide, cyclohexylmagnesium methanesulfonate, cyclohexylmagnesium p-toluenesulfonate, cyclohexylmagnesium methoxide, cyclohexylmagnesium ethoxide, cyclohexylmagnesium tert-butoxide, cyclohexylmagnesium phenoxide, phenylmagnesium chloride, phenylmagnesium bromide, phenylmagnesium iodide, phenylmagnesium methanesulfonate, phenylmagnesium p-toluenesulfonate, phenylmagnesium methoxide, phenylmagnesium ethoxide, phenylmagnesium tert-butoxide, phenylmagnesium phenoxide, p-tolylmagnesium chloride, p-tolylmagnesium bromide, p-tolylmagnesium iodide, p-tolylmagnesium methanesulfonate, p-tolylmagnesium p-toluenesulfonate, p-tolylmagnesium methoxide, p-tolylmagnesium ethoxide, p-tolylmagnesium tert-butoxide, p-tolylmagnesium phenoxide, benzylmagnesium chloride, benzylmagnesium bromide, benzylmagnesium iodide, benzylmagnesium methanesulfonate, benzylmagnesium p-toluenesulfonate, benzylmagnesium methoxide, benzylmagnesium ethoxide, benzylmagnesium tert-butoxide and benzylmagnesium phenoxide.
Preferred specific examples of the magnesium compound represented by the formula (III) include methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, methylmagnesium methanesulfonate, methylmagnesium tert-butoxide, ethylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium iodide, ethylmagnesium methanesulfonate, ethylmagnesium tert-butoxide, propylmagnesium chloride, propylmagnesium bromide, propylmagnesium iodide, propylmagnesium methanesulfonate, propylmagnesium tert-butoxide, iso-propylmagnesium chloride, iso-propylmagnesium bromide, iso-propylmagnesium iodide, iso-propylmagnesium methanesulfonate, iso-propylmagnesium tert-butoxide, n-butylmagnesium chloride, n-butylmagnesium bromide, n-butylmagnesium iodide, n-butylmagnesium methanesulfonate, n-butylmagnesium tert-butoxide, sec-butylmagnesium chloride, sec-butylmagnesium bromide, sec-butylmagnesium iodide, sec-butylmagnesium methanesulfonate, sec-butylmagnesium tert-butoxide, iso-butylmagnesium chloride, iso-butylmagnesium bromide, iso-butylmagnesium iodide, iso-butylmagnesium methanesulfonate, iso-butylmagnesium tert-butoxide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, tert-butylmagnesium iodide, tert-butylmagnesium methanesulfonate, tert-butylmagnesium tert-butoxide, phenylmagnesium chloride, phenylmagnesium bromide, phenylmagnesium iodide, phenylmagnesium methanesulfonate, phenylmagnesium tert-butoxide, p-tolylmagnesium chloride, p-tolylmagnesium bromide, p-tolylmagnesium iodide, p-tolylmagnesium methanesulfonate, p-tolylmagnesium tert-butoxide, benzylmagnesium chloride, benzylmagnesium bromide, benzylmagnesium iodide, benzylmagnesium methanesulfonate and benzylmagnesium tert-butoxide.
Although no particular limitation is imposed on the preparation process of the magnesium compound (III), it can be prepared, for example, by the process as described in D. A. Shirley, Org. React., 8, 28-58(1954) or in a similar manner thereto. Alternatively, a commercially available product may be employed.
The amide compound in the present invention is represented by the following formula (II): 
wherein, R2 represents a hydrogen atom or a lower C1-4 alkyl group, R3 represents (1) a C1-12 alkyl group, (2) a C2-5 alkenyl group, (3) a C1-6 organosilyl group, (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (5) a C6-13 aralkyl group which may be substituted by a lower C1-4 alkyl group, (6) a 5- to 8-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, or (7) a naphthyl group and R4 represents an electron withdrawing group; or R3 and R4 may form a heterocycle together with the adjacent nitrogen atom.
Specific examples of R2 of the amide compound (II) include a hydrogen atom and lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
When R3 of the amide compound (II) represents (1) a C1-12 alkyl group, specific examples of it include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
When R3 represents (2) a C2-5 alkenyl group, specific examples of it include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 2-methylallyl.
When R3 represents (3) a C1-6 organosilyl group, specific examples include tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylhexylsilyl and dimethylthexylsilyl.
When R3 represents (4) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, halogen atoms such as fluorine, chlorine, bromine and iodine and a nitro group.
When R3 represents (5) a C6-13 aralkyl group which may be substituted by a lower C1-4 alkyl group, specific examples of it include C6-13 aralkyl groups such as benzyl, xcex1-phenylethyl, xcex2-phenylethyl, xcex1-phenylpropyl, xcex2-phenylpropyl, xcex3-phenylpropyl and naphthylmethyl. Here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
When R3represents (6) a 5- to 8-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, specific examples of it include 5- to 8-membered alicyclic groups such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
When R3 represents (7) a naphthyl group, specific examples of it include a naphthyl group.
In the present invention, the amide compound represented by the formula (II) is a compound selected from the amide compounds represented by the following formulas (V), (VI) and (VII): 
wherein R2 and R3 have the same meanings as described above, X represents an oxygen atom, a sulfur atom or an NR11 group wherein R11 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted phenyl group, Y represents an oxygen atom or a sulfur atom, R8, R9 and R10 each independently represents (1) a C1-12 alkyl group, (2) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (3) a benzyl group which may be substituted by a lower C1-4 alkyl group, (4) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (5) a naphthyl group, or (6) may form a 4- to 6-membered ring together with R3.
As R2 and R3 of the amide compound (V), (VI) or (VII), those exemplified above as R2 and R3 can be mentioned, respectively.
Specific examples of X of the amide compound (V), (VI) or (VII) include an oxygen atom, a sulfur atom and NR11 groups (here, specific examples of R11 include substituted or unsubstituted C1-12 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl (here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, halogen atoms such as fluorine, chlorine, bromine and iodine, and a nitro group), and substituted or unsubstituted phenyl groups (here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, halogen atoms such as fluorine, chlorine, bromine and iodine, and a nitro group).
In the amide compound (V), (VI) or (VII), Y represents an oxygen atom or a sulfur atom.
In the amide compound (V), (VI) or (VII), when R8, R9 or R10 represents (1) a C1-12 alkyl group, specific examples of it include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
When R8, R9 or R10 represents (2) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, halogen atoms such as fluorine, chlorine, bromine and iodine and a nitro group.
When R8, R9 or R10 represents (3) a benzyl group which may be substituted by a lower C1-4 alkyl group, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
When R8, R9 or R10 represents (4) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, specific examples of it include 5- to 7-membered alicyclic groups such as cyclopentyl, cyclohexyl and cycloheptyl. Specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
When R8, R9 or R10 represents (5) a naphthyl group, specific examples of it include a naphthyl group.
R8, R9 or R10 (6) may form a 4- to 6-membered ring together with R3.
Although no particular limitation is imposed on the preparation process of the amide compound represented by the formula (V), (VI) or (VII), it can be synthesized, for example, by the process as described in WO93/13064 or in a similar manner thereto.
Specific examples of the amide compound of the formula (V) include following compounds:
N-cyclohexyl-N-p-toluenesulfonylpropionamide,
N-cyclopentyl-N-p-toluenesulfonylpropionamide,
N-isopropyl-N-p-toluenesulfonylpropionamide,
N-(tert-butyl)-N-p-toluenesulfonylpropionamide,
N-phenyl-N-p-toluenesulfonylpropionamide,
N-benzyl-N-p-toluenesulfonylpropionamide,
N-[(S)-phenethyl]-N-p-toluenesulfonylpropionamide,
N-[(R)-phenethyl]-N-p-toluenesulfonylpropionamide,
N-cyclohexyl-N-4-methoxybenzenesulfonylpropionamide,
N-cyclohexyl-N-4-tert-butylbenzenesulfonylpropionamide,
N-cyclohexyl-N-2-naphthalenesulfonylpropionamide,
N-cyclohexyl-N-4-bromobenzenesulfonylpropionamide and
N-(4-chlorophenyl)-N-p-toluenesulfonylpropionamide.
Specific examples of the amide compound of the formula (VI) include the following compounds:
methyl N-methyl-N-propionylcarbamate,
methyl N-methyl-N-propionylthiocarbamate,
methyl N-tert-butyl-N-propionylcarbamate,
methyl N-tert-butyl-N-propionylthiocarbamate,
methyl N-phenyl-N-propionylcarbamate and
methyl N-phenyl-N-propionylthiocarbamate.
Specific examples of the amide compound of the formula (VII) include the following compounds:
N-methyl-N-propionylbenzamide,
N-ethyl-N-propionylbenzamide,
N-isopropyl-N-propionylbenzamide and
N-phenyl-N-propionylbenzamide.
Furthermore, the amide compound of the formula (V) is a compound selected from the amide compounds represented by the following formulas (VIII), (IX), (X), (XI) and (XII): 
wherein R2 has the same meaning as described above, W represents an oxygen atom or a sulfur atom, and R12 to R23 are the same or different and each independently represents (1) a hydrogen atom, (2) a C1-12 alkyl group, (3) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (4) a benzyl group which may be substituted by a lower C1-4 alkyl group, (5) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, or (6) a naphthyl group; or (7) any two of R12 to R23 on the same carbon atom may be coupled together to form a C4-6 alkylene group, (8) any two of R12 to R23 on the adjacent carbon atoms may form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxyl group or a halogen atom, (9) any two of R12 to R23 on the adjacent carbon atoms may be coupled together to form a C3-6 alkylene group, or (10) any two of R12 to R23 on the adjacent carbon atoms may form, together with the carbon atoms, a polycyclic group.
As R2 of the amide compound (VIII), (IX), (X), (XI) or (XII), those exemplified above as R2 can be mentioned.
Specific examples of W of the amide compound (VIII), (IX), (X), (XI) or (XII) include an oxygen atom and a sulfur atom.
Examples of R12 to R23 of the amide compound (VIII), (IX), (X), (XI) or (XII) include (1) a hydrogen atom.
Specific examples of (2) the C1-12 alkyl group represented by R12 to R23 include those exemplified above with respect to R8, R9 or R10.
Specific examples of (3) the phenyl group, as R12 to R23, which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom include those exemplified above with respect to R8, R9 or R10.
Specific examples of (4) the benzyl group, as R12 to R23, which may be substituted by a lower C1-4 alkoxy group include those exemplified above with respect to R8, R9 or R10.
Specific examples of (5) the 5- to 7-membered alicyclic group, as R12 to R23, which may be substituted by a lower C1-4 alkyl group include those exemplified above with respect to R8, R9 or R10.
Specific examples of (6) the naphthyl group include that exemplified above with respect to R8, R9 or R10.
When in R12 to R23, (7) any two of R12 to R23 on the same carbon atom are coupled together to form a C4-6 alkylene group, specific examples include C4-7 alkylene groups such as 1,4-butylene, 1,5-pentylene, 1,6-hexylene and 1,7-heptylene. Specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
When in R12 to R23, (8) any two of R12 to R23 on the adjacent carbon atoms form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxyl group or a halogen atom, specific examples include aromatic rings which may have a substituent (here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, halogen atoms such as fluorine, chorine, bromine and iodine) such as benzene, naphthalene, phenanthrene, furan, thiophene, benzofuran, isobenzofuran, pyrrole, pyridine, pyrimidine, pyrazine, pyridazine, indole, isoindole, quinoline and isoquinoline rings.
When in R12 to R23, (9) any two of R12 to R23 on the adjacent carbon atoms are coupled together to form a C3-6 alkylene group, specific examples include C3-6 alkylene groups which may have a substituent (here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, halogen atoms such as fluorine, chorine, bromine and iodine and aryl groups) such as 1,3-propylene, 1,4-butylene, 1,5-pentylene and 1,6-hexylene.
When in R12 to R23, (10) any two of R12 to R23 on the adjacent carbon atoms form, together with the carbon atoms, a polycyclic group, specific examples include polycyclic groups which may have a substituent (here, specific examples of the substituent include lower C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, lower C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, and halogen atoms such as fluorine, chorine, bromine and iodine) such as indane, norbornane and 1,2,3,4-tetrahydronaphthalene.
Although there is no particular limitation imposed on the preparation process of the amide compound of the formula (VIII), it can be synthesized, for example, by acylating the amine compound available by the process described in U.S. Pat. No. 3,345,374 in a known manner.
Specific examples of the amide compound of the formula (VIII) include N-propionyl-2-oxa-1,3-sultam and N-propionyl-1,2-benzisothiazole-2,3-dihydro-3-methyl-1,1-dioxide.
Although there is no particular limitation imposed on the preparation process of the amide compound of the formula (IX), it can be synthesized, for example, by the process described in Wolfgang Oppolzer, et al., Tetrahedron Letters, 31, 4117(1990) or in a similar manner thereto.
Specific examples of the amide compound of the formula (IX) include N-propionyl-bornane-10,2-sultam.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (X), it can be synthesized, for example, by ketalizing phenol-2-sulfonamide available by the process described in Peter F. Drygala, et al., Synthetic Communications, 24, 4117(1994) in a conventional manner and then acylating the resulting amide compound in a known manner.
Specific examples of the amide compound of the formula (X) include N-propionyl-4,1,2-benzoxathiazine-2,3-dihydro-3-methyl-1,1-dioxide.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XI), it can be synthesized, for example, by acylating in a known manner the amine compound available by the process described in WO9205164.
Specific examples of the amide compound of the formula (XI) include N-propionyl-1H-4,2,1-benzoxathiazine-2,2-dioxide.
Although there is no particular limitation imposed on the preparation process of the amide compound of the formula (XII), it can be synthesized, for example, by acylating in a known manner the amine compound available by the process described in U.S. Pat. No. 3,303,189.
Specific examples of the amide compound of the formula (XII) include N-propionyl-2,1-benzothiazine-2,2-dioxide.
Furthermore, in the present invention, the amide compound of the formula (VI) is a compound selected from the amide compounds represented by the formula (XIII), (XIV) and (XV): 
wherein R2, X and Y have the same meanings as described above, Q represents an oxygen atom or a sulfur atom, and R24 to R31 are the same or different and each independently represents (1) a hydrogen atom, (2) a C1-12 alkyl group, (3) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro group or a halogen atom, (4) a benzyl group which may be substituted by a lower C1-4 alkyl group, (5) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group, or (6) a naphthyl group; or (7) any two of R24 to R31 on the same carbon atom may be coupled together to form a C4-6 alkylene group, (8) any two of R24 to R31 on the adjacent carbon atoms may form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxyl group or a halogen atom, (9) any two of R24 to R31 on the adjacent carbon atoms may be coupled together to form a C3-6 alkylene group, or (10) any two of R24 to R31 on the adjacent carbon atoms may form, together with the carbon atoms, a polycyclic group.
As R2, X and Y of the amide compound (XIII), (XIV) or (XV), those exemplified above as R2, X and Y can be mentioned, respectively.
As Q of the amide compound (XIV), those exemplified above as W can be mentioned.
As R24 to R31 of the amide compound (XIII), (XIV) or (XV), those exemplified above with respect to R12 to R23 can be mentioned.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XIII), it can be synthesized by the process described in, for example, JP-A-63-10765, JP-A-62-252786, JP-A-63-284176, JP-A-2-292269, JP-A-2-788, JP-A-61-275267, JP-A-62-169781, JP-A-62-77384, JP-A-63-170377, JP-A-62-246550 or JP-A-6-65195 or in a similar manner thereto.
Specific examples of the amide compound of the formula (XIII) include 4-methyl-3-propionyloxazolidin-2-one, 4,4-dimethyl-3-propionyloxazolidin-2-one, 4-phenyl-3-propionyloxazolidin-2-one, 4-benzyl-3-propionyloxazolidin-2-one, 4-isopropyl-3-propionyloxazolidin-2-one, 3-propionyl-(3aS-cis)-3,3a,8,tetrahydro-2H-indeno[1,2-d]oxazol-2-one and 3-propionyl-(3aR-cis)-3,3a,8,tetrahydro-2H-indeno[1,2-d]oxazol-2-one.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XIV) or (XV), it can be synthesized, for example, by the process described in Malcom R. banks, et al., Tetrahedron, 48, 7979(1992) or in a similar manner thereto.
Specific examples of the amide compound of the formula (XIV) include N-propionyl-tetrahydro-1,5,3-dioxazin-2-one.
Specific examples of the amide compound of the formula (XV) include N-propionyl-4,4-dimethyl-tetrahydro-1,3-oxazin-2-one and N-propionyl-tetrahydro-1,3-oxazin-2-one-4,4-dimethyl.
Furthermore, in the present invention, the amide compound represented by the formula (VII) is a compound selected from the amide compounds represented by the following formulas (XVI), (XVII), (XVIII), (XIX), (XX) and (XXI): 
wherein R2 and X have the same meanings as described above, U represents an oxygen atom or a sulfur atom, and R32 to R47 are the same or different and each independently represents (1) a hydrogen atom, (2) a C1-12 alkyl group, (3) a phenyl group which may be substituted by a lower C1-4 alkyl group, a lower C1-4 alkoxy group, a nitro atom or a halogen atom, (4) a benzyl group which may be substituted by a lower C1-4 alkyl group, (5) a 5- to 7-membered alicyclic group which may be substituted by a lower C1-4 alkyl group or (6) a naphthyl group; or (7) any two of R32 to R47 on the same carbon atom may be coupled together to form a C4-6 alkylene group, (8) any two of R32 to R47 on the adjacent carbon atoms may form, together with the carbon atoms, an aromatic ring which may have a substituent wherein said substituent is a lower C1-4 alkyl group, a lower C1-4 alkoxy group, an aryl group, a hydroxyl group or a halogen atom, (9) any two of R32 to R47 on the adjacent carbon atoms may be coupled together to form a C3-6 alkylene group, or (10) any two of R32 to R47 on the adjacent carbon atoms may form, together with the carbon atoms, a polycyclic group.
As R2 and X of the amide compound (XVI), (XVII) (XVIII), (XIX), (XX) or (XXI), those exemplified above as R2 and X can be mentioned, respectively.
As U of the amide compound (XVI), (XVII), (XVIII), (XIX), (XX) or (XXI), those exemplified above as W can be mentioned.
As R32 to R47 of the amide compound (XVI), (XVII), (XVIII), (XIX), (XX) or (XXI), those exemplified above with respect to R12 to R23 can be mentioned.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XVI), it can be synthesized by acylating a commercially available amine compound in a known manner.
Specific examples of the amide compound of the formula (XVI) include N-propionyl-3,3,4,4-tetramethylazetidin-2-one and N-propionyl-azetidin-2-one.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XVII), it can be synthesized by acylating a commercially available amine compound in a known manner.
Specific examples of the amide compound of the formula (XVII) include 5,5-dimethyl-3-propionyl-2,2-pentamethyleneoxazolidin-4-one, 2,2-dibenzyl-5,5-dimethyl-3-propionyloxazolin-4-one.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XVIII), it can be synthesized, for example, by the process described in JP-A-6-65195 or in a similar manner thereto.
Specific examples of the amide compound of the formula (XVIII) include 1-propionyl-5,5-dimethylpyrrolidin-2-one, 1-propionyl-5,5-diethylpyrrolidin-2-one, 1-propionyl-5,5-diisopropylpyrrolidin-2-one.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XIX), it can be synthesized, for example, by the process described in JP-A-7-70116, JP-A-7-97381 or JP-A-7-165760, or in a similar manner thereto.
Specific examples of the amide compound of the formula (XIX) include 5,5-dimethyl-3-propionyl-2,2-pentamethyleneoxazin-4-one, 3-propionyl-spiro[2,3-dihydro-4H-1,3-benzoxazin-2,1xe2x80x2-cyclohexan]-4-one, 3-propionyl-spiro[2,3-dihydro-4H-1,3-naphthoxazine-2,1xe2x80x2-cyclohexan]-4-one.
Although no particular limitation is imposed on the amide compound of the formula (XX), it can be synthesized, for example, by acylating, in a known manner, an amine compound available by the process described in JP-A-63-295567 or in a similar manner thereto.
Specific examples of the amide compound of the formula (XX) include N-propionyl-3,4-dihydro-2H-1,4-benzoxazin-3-one.
Although no particular limitation is imposed on the preparation process of the amide compound of the formula (XXI), it can be synthesized., for example, by the process described in JP-A-7-97381 or in a similar manner thereto.
Specific examples of the amide compound of the formula (XXI) include N-propionyl-4H-isoquinolizin-1-one.
Although no particular limitation is imposed on the process for synthesizing the amide compound of the formula (II) from an amine compound, it can be synthesized by the process described in JP-A-7-97381 or in a similar manner thereto.
For example, the amide compound represented by the formula (II) can be prepared by reacting a compound represented by the following formula (IIa):
xe2x80x83HNR3R4xe2x80x83xe2x80x83(IIa)
wherein R3 and R4 have the same meanings as described above with a compound of the following formula (IIb):
R2CH2COOHxe2x80x83xe2x80x83(IIb)
wherein R2 has the same meaning as described above or a reactive derivative thereof.
The reaction of the compound (IIa) with the compound (IIb) can be carried out in a proper solvent in the presence of a dehydrating agent. Examples of the dehydrating agent include carbonyldiimidazole dicyclohexylcarbodiimide, N-hydroxysuccinimide and 1-hydroxybenzothiazole. Preferred examples of the solvent include diethyl ether, methylene chloride, tetrahydrofuran and acetonitrile. This reaction is carried out at a temperature of xe2x88x9230 to 70xc2x0 C., preferably 0 to 30xc2x0 C.
The reaction of the compound (IIa) with a reactive derivative of the compound (IIb) can be carried out in a proper solvent in the presence or absence of a base. As the reactive derivative, acid halides and acid anhydrides can be employed suitably. Examples of the base include alkali metal hydrides, alkali metals, lower alkyl and aryl lithium compounds, and organic bases such as pyridine, di(lower alkyl)anilines and tri(lower alkyl)amines. Preferred examples of the solvent include tetrahydrofuran, diethyl ether, benzene, toluene, methylene chloride and chloroform. This reaction is usually carried out at xe2x88x9280 to 50xc2x0 C., preferably xe2x88x9220 to 30xc2x0 C.
The preparation process according to the present invention will hereinafter be described specifically.
The preparation process of the present invention can be carried out reacting an amide compound of the formula (II) with a magnesium compound of the formula (III) in an organic solvent in an inert gas atmosphere such as argon or nitrogen, thereby producing the corresponding enolate (IIc) and then reacting the enolate (IIc) with an azetidinone compound of the formula (I), whereby a 4-substituted azetidinone compound of the formula (IV) can be prepared. 
wherein R, R1, R2, R3, R4, R5, R6 and Z have the same meaning as described above.
As the solvent, inert solvents which do not take part in the reaction can be employed. Preferred examples include organic solvents, for example, hydrocarbon solvents such as pentane, hexane and heptane, chlorine solvents such as methylene chloride and chloroform, aromatic solvents such as benzene, chlorobenzene, toluene and xylene, and ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, 1,3-dioxolane and dioxane; mixtures thereof.
Concerning the reaction temperature, the reaction for the preparation of the enolate (IIc) and the reaction of the enolate (IIc) with the azetidinone derivative (I) are each carried out at xe2x88x9250 to 100xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C.
Concerning the reaction time, the reaction for the preparation of the enolate (IIc) and the reaction of the enolate (IIc) with the azetidinone derivative (I) are each carried out for 10 to 180 minutes, preferably 30 to 90 minutes.
Concerning the molar ratio, the amide compound of the formula (II) and the magnesium compound of the formula (III) are used each in an amount of 1 to 8 moles relative to 1 mole of the azetidinone derivative of the formula (I).
More preferably, the amide compound of the formula (II) and the magnesium compound of the formula (III) are used in amounts of 1 to 3 moles and 1 to 4 moles, respectively, relative to 1 mole of the azetidinone derivative of the formula (I).
When R2 represents an alkyl group such as methyl, the xcex1-form and the xcex2-form so prepared differ in the ratio, depending on the kind of the amide compound of the formula (II), the kind of the magnesium compound of the formula (III), or the molar ratio. After the completion of the reaction, the desired product can be isolated by the ordinary post treatment.
It is also possible to subject the compound of the formula (IV) available by the preparation process of the present invention to hydrolysis after isolation or without isolation, thereby introducing into the corresponding carboxylic acid derivative represented by the formula (Ixe2x80x2): 
wherein R, R1 and R2 have the same meanings as described above.